Clinical and electrophysiologic effects of intravenous dofetilide (UK-68,798), a new class III antiarrhythmic drug, in patients with angina pectoris

Sedgwick, Martin L.; Rasmussen, Henrik; Cobbe, Stuart M.

doi:10.1016/0002-9149(92)90996-c

Cited by 61 publications

(21 citation statements)

References 16 publications

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“…15 In addition, dofetilide does not affect cardiac conduction or sinus-node function in patients with preexisting cardiac disease. 15,16 In patients with atrial fibrillation, dofetilide has been shown to restore and maintain sinus rhythm. 17,18,24 We designed the Danish Investigations of Arrhythmia and Mortality on Dofetilide in Congestive Heart Failure (DIAMOND-CHF) Study to evaluate whether dofetilide affects survival or morbidity among patients with reduced left ventricular function and congestive heart failure.…”

Section: Discussionmentioning

confidence: 99%

Dofetilide in Patients with Congestive Heart Failure and Left Ventricular Dysfunction

et al. 1999

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Section: Discussionmentioning

confidence: 99%

Dofetilide in Patients with Congestive Heart Failure and Left Ventricular Dysfunction

et al. 1999

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“…When administered to patients undergoing electrophysiological studies, 19,[47][48][49] the primary effects of dofetilide are seen on the refractory periods of atrial and ventricular muscle. Dofetilide has no effect on PR, QRS, or HV intervals.…”

Section: Clinical Studiesmentioning

confidence: 99%

Dofetilide

2000

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Dofetilide is a new antiarrhythmic drug that recently was recommended for approval by an advisory committee to the Food and Drug Administration (FDA) for treatment of patients with persistent atrial fibrillation. Dofetilide is a specific blocker of the rapid component of the outward delayed rectifier potassium current I Kr and will represent the first drug with relatively pure class III antiarrhythmic properties to be widely released. Basic ElectrophysiologyCardiac depolarization results principally from the flow of inward Na ϩ and Ca 2ϩ ions as the rapid and slow inward currents. Repolarization results from a balance between inactivation of the slow inward current and activation of repolarizing predominantly K ϩ currents. Early repolarization results from a transient outward current, I TO , which is activated rapidly by membrane depolarization. Terminal repolarization is mediated by outward delayed rectifier K ϩ currents, I K , which are activated slowly (over a period of 200 to 300 ms) on membrane depolarization and turn off, or deactivate, relatively slowly on membrane repolarization.I K can be separated pharmacologically into 2 components: a rapidly activating component, I Kr , and a slower component, I Ks , each carried by a separate ion channel molecule. 1,2 HERG channels are responsible for I Kr , whereas I Ks flows through KvLQT1 channels. Specific blockers of I Kr are therefore classified as pure class III antiarrhythmic agents because they produce only prolongation of action potential duration (and hence of QT interval). These actions may result in arrhythmia termination or suppression but can also lead to excess QT prolongation and polymorphic ventricular tachycardia. Examples of specific I Kr blockers include the methanesulfonanilide agents dofetilide, E4031, almokalant, and D-sotalol. Effects of Dofetilide on I krDofetilide blocks I Kr in all myocardial tissues with high potency (50% effective concentration [EC 50 ] in the nanomolar range). Block is voltage dependent and most prominent at depolarized potentials. 1,3,4 It does not occur in resting muscle but rather develops on depolarization. 1,5 Recovery from block is also potential dependent and is very slow at hyperpolarized potentials close to the resting potential. 1 Steady-state block at any dose is constant and does not change with increasing heart rate 1,3 because the recovery time is much greater than the diastolic interval. 1 Dofetilide block of I Kr increases as extracellular potassium concentration ([K]o) is reduced. 6 This sensitivity of dofetilide block to [K]o is of obvious clinical importance. Even moderate hypokalemia would be expected to disproportionately increase action potential prolongation induced by dofetilide, and correction of hypokalemia is of crucial importance in treating QT prolongation and torsade de pointes caused by I Kr blockade. Conversely, hyperkalemia blunts the effect of dofetilide, 7 suggesting the possibility of reduced efficacy after acute coronary occlusion or during rapid heart rates, when local cardiac tis...

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“…Most potent blockers of I Kr (e.g., dofetilide, E4031) prolong cardiac APD in a reverse-frequency-dependent manner: the faster the heart rate, the less the prolongation of APD (Carmeliet, 1992;Sedgwick et al, 1992;Jurkiewicz and Sanguinetti, 1993). The mechanism of this frequency profile is uncertain, but is not caused by frequencydependent block of I Kr (Jurkiewicz and Sanguinetti, 1993).…”

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Open Channel Block of HERG K⁺ Channels by Vesnarinone

et al. 2001

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Vesnarinone, a cardiotonic agent, blocks I(Kr) and, unlike other I(Kr) blockers, produces a frequency-dependent prolongation of action potential duration (APD). To elucidate the mechanisms, we studied the effects of vesnarinone on HERG, the cloned human I(Kr) channel, heterologously expressed in Xenopus laevis oocytes. Vesnarinone caused a concentration-dependent inhibition of HERG currents with an IC(50) value of 17.7 +/- 2.5 microM at 0 mV (n = 6). When HERG was coexpressed with the beta-subunit MiRP1, a similar potency for block was measured (IC(50): 15.0 +/- 3.0 microM at 0 mV, n = 5). Tonic block of the HERG channel current was minimal (<5% at 30 microM, n = 5). The rate of onset of block and the steady-state value for block of current were not significantly different for test potentials ranging from -40 to +40 mV [time constant (tau) = 372 +/- 76 ms at +40 mV, n = 4]. Recovery from block at -60, -90, and -120 mV was not significantly different (tau = 8.5 +/- 1.5 s at -90 mV, n = 4). Vesnarinone produced similar effects on inactivation-removed mutant (G628C/S631C) HERG channels. The IC(50) value was 10.7 +/- 3.7 microM at 0 mV (n = 5), and the onset and recovery from block of current findings were similar to those of wild-type HERG. Amino acids important for the binding of vesnarinone were identified using alanine-scanning mutagenesis of residues believed to line the inner cavity of the HERG channel. Six important residues were identified, including G648, F656, and V659 located in the S6 domain and T623, S624, and V625 located at the base of the pore helix. These residues are similar but not identical to those determined previously for MK-499, an antiarrhythmic drug. In conclusion, vesnarinone preferentially blocks open HERG channels, with little effect on channels in the rested or inactivated state. These actions may contribute to the favorable frequency-dependent prolongation in APD.

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Clinical and electrophysiologic effects of intravenous dofetilide (UK-68,798), a new class III antiarrhythmic drug, in patients with angina pectoris

Cited by 61 publications

References 16 publications

Dofetilide in Patients with Congestive Heart Failure and Left Ventricular Dysfunction

Dofetilide in Patients with Congestive Heart Failure and Left Ventricular Dysfunction

Dofetilide

Open Channel Block of HERG K⁺ Channels by Vesnarinone

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Clinical and electrophysiologic effects of intravenous dofetilide (UK-68,798), a new class III antiarrhythmic drug, in patients with angina pectoris

Cited by 61 publications

References 16 publications

Dofetilide in Patients with Congestive Heart Failure and Left Ventricular Dysfunction

Dofetilide in Patients with Congestive Heart Failure and Left Ventricular Dysfunction

Dofetilide

Open Channel Block of HERG K+ Channels by Vesnarinone

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Open Channel Block of HERG K⁺ Channels by Vesnarinone